Membrane-in-the-middle optomechanics with a soft-clamped membrane at milliKelvin temperatures

Soft-clamped silicon nitride membrane resonators reach coherence times tau in excess of 100 ms at milliKelvin bath temperatures. However, harnessing strong optomechanical coupling in dry dilution refrigerators remains challenging due to vibration issues and heating by optical absorption. Here, we propose to address these issues with an actuator-free optical cavity and mechanical resonator design, in which the cavity is mounted on a simple vibration-isolation platform. We observe dynamical backaction when the cavity is driven with a free-space optical beam stabilized close to the red sideband using a two-beam locking scheme. Finally, we characterize the effect of absorption heating on the coherence time, and find a scaling with the intracavity power P as tau proportional to P to the power of -(0.34+/-0.04)

Laser cooling a membrane-in-the-middle system close to the quantum ground state from room temperature

Many protocols in quantum science and technology require initializing a system in a pure quantum state. In the context of the motional state of massive resonators, this enables studying fundamental physics at the elusive quantum–classical transition, and measuring force and acceleration with enhanced sensitivity. Laser cooling has been a method of choice to prepare mechanical resonators in the quantum ground state, one of the simplest pure states. However, to overcome the heating and decoherence by the thermal bath, this usually has to be combined with cryogenic cooling. Here, we laser-cool an ultracoherent, soft-clamped mechanical resonator close to the quantum ground state directly from room temperature. To this end, we implement the versatile membrane-in-the-middle setup with one fiber mirror and one phononic crystal mirror, which reaches a quantum cooperativity close to unity already at room temperature. We furthermore introduce a powerful combination of coherent and measurement-based quantum control techniques, which allows us to mitigate thermal intermodulation noise. The lowest occupancy we reach is 30 phonons, limited by measurement imprecision. Doing away with the necessity for cryogenic cooling should further facilitate the spread of optomechanical quantum technologies

Membrane-Based Scanning Force Microscopy

We report the development of a scanning force microscope based on an ultrasensitive silicon nitride membrane optomechanical transducer. Our development is made possible by inverting the standard microscope geometry - in our instrument, the substrate is vibrating and the scanning tip is at rest. We present topography images of samples placed on the membrane surface. Our measurements demonstrate that the membrane retains an excellent force sensitivity when loaded with samples and in the presence of a scanning tip. We discuss the prospects and limitations of our instrument as a quantum-limited force sensor and imaging tool.</p

Modern American populism: Analyzing the economics behind the Silent Majority, the Tea Party and Trumpism

This article researches populism, more specifically, Modern American Populism (MAP), constructed of white, rural, and economically oppressed reactionarianism, which was borne out of the political upheaval of the 1960’s Civil Rights movement. The research looks to explain the causes of populism and what leads voters to support populist movements and politicians. The research focuses on economic anxiety as the main cause but also examines an alternative theory of racial resentment. In an effort to answer the question, what causes populist movements and motivations, I apply a research approach that utilizes qualitative and quantitative methods. There is an examination of literature that defines populism, its causes and a detailed discussion of the case studies, including the 1972 election of Richard Nixon; the Tea Party election of 2010; and the 2016 election of Donald Trump. In addition, statistical data analysis was run using American National Election Studies (ANES) surveys associated with each specific case study. These case studies were chosen because they most represent forms of populist movements in modern American history. While ample qualitative evidence suggested support for the hypothesis that economic anxiety is a necessary condition for populist voting patterns that elected Nixon, the Tea Party and Trump, the statistical data only supported the hypothesis in two cases, 2010 and 2016, with 1972 coming back inconclusive. The data also suggested that both economic anxiety and racial resentment played a role in 2010 and 2016, while having no significant effect in 1972 in either case. This suggests that further research needs to be conducted into additional populist case studies, as well as an examination into the role economic anxiety and economic crises play on racial resentment and racially motivated voting behavior

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response

The evolution of non-small cell lung cancer metastases in TRACERx

Metastatic disease is responsible for the majority of cancer-related deaths. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse

Genomic–transcriptomic evolution in lung cancer and metastasis

Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic–transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary–metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Modeling and Observation of Nonlinear Damping in Dissipation-Diluted Nanomechanical Resonators

Dissipation dilution enables extremely low linear loss in stressed, high aspect ratio nanomechanical resonators, such as strings or membranes. Here, we report on the observation and theoretical modeling of nonlinear dissipation in such structures. We introduce an analytical model based on von Kármán theory, which can be numerically evaluated using finite-element models for arbitrary geometries. We use this approach to predict nonlinear loss and (Duffing) frequency shift in ultracoherent phononic membrane resonators. A set of systematic measurements with silicon nitride membranes shows good agreement with the model for low-order soft-clamped modes. Our analysis also reveals quantitative connections between these nonlinearities and dissipation dilution. This is of interest for future device design and can provide important insight when diagnosing the performance of dissipation dilution in an experimental setting.ISSN:0031-9007ISSN:1079-711